Synthesis of a-ring aromatic steroids

ABSTRACT

Total synthesis of steroids of the estrone and equilenin series involving conjugate 1,4-addition of a meta-substituted benzyl organometallic reagent to a C/D bicyclic methylene ketone. An aromatization of the B-ring of Delta 9(11) estrone derivatives.

lUME lull States Patent @ulten ec. 24, 1974 SYNTHESIS OF A-RING AROMATIC[56] References Cited STEROIDS UNITED STATES PATENTS [75] Inventor: NoalCohe Mo c a -J- 2,835,698 6/1958 Magerlein et al 260/590 AssigneezHoiimanmLa Roche Inc. y 3,373,206 3/1968 Rocca 260/590 NJ. PrimaryExaminer-Daniel D. Horwitz Flledi J y 2, 1973 Attorney, Agent, orFirm-Samuel L. Welt; Jon S. Saxe; George [63] C Related. U.S. Azpicatign D2215: 032 O 4 [57] ABSTRACT I t t. gy i m par 0 er 0 C Totalsynthesis of Steroids of the estrone and equilenm Series involvingconjugate 1,4-additi0n of a meta- 52 us. c1 260/590, 260/333, 260/345.9,Substituted benlyl organometallic reagent to 260/3478, 260/3975 A cyclicmethylene ketone. An aromatization 0f the B- 51 Int. Cl. C07C 49/82 ringof A estrone derivatives- Fieldl of Search 260/590 9 Claims, N0 Drawingsl SYNTHESIS OF A-RING AROMATI C STEROIDS RELATED APPLICATIONS Thisapplication is a continuation-in-part of copending U.S. Pat. ApplicationSer. No. 295,032, filed Oct. 4, 1972.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to aprocess for the preparation of steroids starting with a C/D bicyclicintermediate. 'In particular, the types of steroids which may besynthesized by means of the present process are those having an aromaticA-ring such as estrone, estrone methyl ether, and so forth; and thosesteroids having both the A and B-ring aromatic such as equilenin andequilenin methyl ether. Aromatic steroids such as those aforementionedare naturally occurring hormones which possess a wide range ofbiological activity and are also useful for the preparation of othercompounds of the steroid type, for example 19- norsteroids.

As used throughout the specification and the appended claims, the termlower alkyl denotes a saturated group consisting solely of carbon andhydrogen having a straight chain of from 1 to 8 carbon atoms. Examplesof such groups are methyl, ethyl, butyl, hexyl, octyl, and the like. Theterm tertiary lower alkyl denotes a saturated group consisting solely ofcarbon and hydrogen having its valence from a carbon bound to threeother carbon atoms. Examples of such groups include tertiary butyl,tertiary amyl, and so forth. The term halogen" refers to chlorine,bromine and iodine and the term halide refers to the negative ionsthereof. The term lower alkylene" refers to a divalent saturatedhydrocarbon group having its two valences to two different groups.Examples of such groups are methylene, ethylene, l,2-pro pylene,1,3-propylene, 1,4-butylene, 1,5-pentylene, and so forth.

In the formulae presented herein, the relative stereochemistry of thevarious substituents on the cyclic nucleus is indicated by one of threenotations: a solid line indicating the substituent is in theB-orientation, i.e., above the plane of the molecule; a dotted lineindicating the substituent is in the a-orientation, i.e., below theplane of the molecule; or a wavy line indicating the substituent may beeither in the aor B-configuration or may be a mixture of both.

For convenience, the stereochemistry of the substituent R at the C-13position has been arbitrarily indicated as the B-orientation; thus allthe compounds are depicted as having the natural absolute configuration.It should be understood that the invention described herein is equallyapplicable to compounds having either the natural or the unnaturalconfiguration, for example, to racemic mixtures.

If it is desired to prepare optically active steroids, one may eitherbegin with a known optically active compound of Formula I wherein R islower alkyl, R is tertiary lower alkyl, or a group of the formulawherein R is hydrogen or lower alkyl, R and R each taken independentlyare lower alkyl, and R and R taken together are lower alkylene of from 3to 6 carbon atoms, or alternatively, one may start with a racemiccompound of Formula I and may carry out an optical resolution at one ofthe intermediate stages, or at the stage of the final product by methodsknown per se.

Among the groups that may be specifically mentioned for R aretert-butyl, tetrahydrofuran-2-yl, tetrahydropyran-2-yl, methoxymethyl,2-(2-methoxy)- isopropyl, and so forth.

In the process of the present invention, it is preferred that R, i.e.,the substituent in the l3-position, be methyl or ethyl, most preferably,methyl; and that the substituent R be tertiary butyl.

The final step in the present process involves the conjugate1,4-addition of a meta substituted benzyl moiety derived from anorganometallic agent of the formula wherein R" is lower alkyl, tertiarylower alkyl, benzyl, diphenylmethyl or trityl, and M is magnesiumhalide, lithium or copper, to a methylene ketone of Formula I. In thisstep, all of the carbon atoms necessary to form the steroid nucleus arecombined into the steroid precursor of Formula II wherein R, R and R areas above. It is preferred that the R" substituent on the organometallicagent be methyl or benzyl.

Methylene ketones of Formula I are well-known compounds in theliterature (see, for example, British Pat. No. 1,244,918) and have beenused as versatile intermediates for other types of steroid synthesis.The metallic groups represented by M are magnesium halide, lithium andcopper and the reagents prepared therefrom are referred to,respectively, as Grignard reagents, organolithium reagents andorganocopper reagents. Preparation of Grignard reagents andorganolithium reagents from the corresponding substituted benzyl halidesis by methods known per se (reaction with magnesium or lithium metal),and these reagents prepared in situ may be used directly for theaddition reaction. The use of Grignard reagents is preferred.

The addition reaction of the organometallic reagent, where M ismagnesium halide or lithium, to the methylene ketone is carried out inthe presence of cuprous ion. The cuprous ion is conveniently derivedfrom a euprous halide, most preferably having the same halogen as thatfrom which the organometallic reagent was prepared. The amount ofcuprous halide utilized in the present reaction can vary from less than1 mole up to about 500 mole with respect to methylene ketone l. The useof between about 50 and 300 mole cuprous halide is preferred.

It is believed that the Grignard or organolithium reagent reacts withthe cuprous ion to form an organocopper reagent (M is copper) in situand that it is this species which adds to the methylene ketone.

Organometallic reagents when M is copper (organocopper reagents) mayalso be pre-formed by reaction of a Grignard or organolithium reagentwith a euprous halide. The pre-formed reagent may then be used to reactwith the methylene ketone of Formula I.

Suitable solvents for the present addition reaction are inert organicsolvents and include organic ethers, e.g., diethyl ether ortetrahydrofuran; hydrocarbons, e.g., pentane, hexane, toluene, and soforth; or mixtures of the above. If a Grignard reagent is utilized, itis most preferable to employ a solvent consisting mainly of an ether,whereas, if an organolithium reagent is utilized, it is most preferableto use a solvent consisting mainly of hydrocarbons, since these arenormally solvents in which the reagents are prepared.

The temperature of the addition reaction is not critical, but it ispreferred to employ a temperature between about 30 and +30C. Normally,to achieve the best results, it is preferable to use an excess of theorganometallic reagent over over the methylene ketone. A molar excess offrom about 5 to fold is especially preferred.

After the completion of the addition reaction, the reaction mixture ishydrolyzed in an aqueous medium. It is preferred that the aqueous mediumcontain an acid, most preferably a mineral acid such as sulfuric orhydrochloric acid. In this manner, metallic salts of the product, aswell as any excess organometallic reagent, are decomposed and thereaction product can be easily isolated, for example, by extraction.

The compound of Formula II is normally produced in two epimeric forms: a4 a-H (axial side chain) and a more stable 4 B-I-I (equatorial sidechain) form. The former epimer can be isomerized, if desired, to thelatter (more stable) one by base treatment, e.g., by treatment with analkali metal hydroxide at elevated temperature, thus avoiding a physicalseparation of these epimers by, e.g., chromatography.

In the next step, the addition product (II), where R is tertiary loweralkyl can be cyclized to a tetracyclic steroid (Illa) OR!!! R v T l l aO H I K IIIu wherein R and R are as above, and R' is tertiary loweralkyl, without loss of the protecting group in the l7-position. Suitableconditions for this cyclization involve the treatment of compound IIwith a mineral acid or organic sulfonic acid at low temperature. Eitherpure 4 B-H epimer of Formula II, or a mixture of epimers can be used forthis reaction.

Suitable acids for the practice of this cyclization include mineralacids such as hydrochloric acid, hydrobromic acid, sulfuric acid, andthe like; and sulfonic acids such as methanesulfonic acid orp-toluenesulfonic acid, and the like. The concentration of the acid inthe total reaction medium should not exceed 4 N and can be as low as 0.5N. Suitable solvents for this cyclization reaction include alcohols suchas methanol and ethanol, and mixtures of the above with water.

The temperature of the cyclization reaction is somewhat critical andcare must be taken that the temperature be kept between about 0 andabout 30C, so that the protecting group in the l7-position is nothydrolyzed.

Where R is other than tertiary lower alkyl, the compound of formula IIcan be cyclized to that of Formula IIIb IIIb wherein R and R" are asabove. In this case, the R group is cleaved to afford a 178 hydroxygroup. The reaction conditions can be the same as for the conversion llIlla, or the temperature and acid concentration can be higher, forexample, temperatures up to about maybe employed.

Compounds of Formulas Illa or lllb can then be converted to knownsteroids such as estrone methyl ether by a further sequence ofreactions.

Starting with a compound of Formula Illa, the 9(1 1) double bond isreduced to afford the compound of Formula IV wherein R, R and R' are asabove. Methods for reduction of this double bond are known per se andinclude catalytic hydrogenation, for example, hydrogenation over apalladium on carbon catalyst in an inert organic solvent such as ethylacetate. Alternatively, the double bond can be chemically reduced usingwell-known conditions such as lithium in ammonia in the presence of anadded amine such as aniline. The protective tertiary lower alkyl groupR' can be removed in the next step by treatment with a strong acid toafford a compound of formula V wherein R and R" are as above.

Suitable methods for removing this protecting group include treatment ofthe compound with a mineral acid such as hydrochloric acid or sulfuricacid or with an organic sulfonic acid such as P-toluene sulfonic acid atelevated temperature, for example, between about 50 and lC in a suitablesolvent, for example, a hydrocarbon such as toluene.- Alternatively, theprotecting group can be removed. by treatment with trifluoroacetic acidat a low temperature, for example, about 0 to about 30C, followed byalkali treatment to remove any trif luoroacetate ester formed.

Alternatively, a compound of Formula V can be prepared directly from acompound of Formula IlIb by catalytic hydrogenation or chemicalreduction, as described above for the conversion Illa IV.

The 3-ether of estradiol (V) can be converted to the correspondingl7-ketone VI wherein R and R are as above, by standard oxidationtechniques such as oxidation with chromium Vl compounds,,for example,Jones reagent, according to methods known per se.

It has been discovered that where R is a tertiary lower alkyl protectinggroup, its removal from com pound Illa (which still contains the 9(1 1)double bond) leads to a novel and unexpected aromatization of the B-ringleading to equilenin derivatives of Formula VII wherein'R and R" are asabove. This reaction may be carriedout in one embodiment by treatment ofthe compound of Formula Illa with a mineral acid such as hydrochloricacid or sulfuric acid, or with or organic sulfonic acid such as'p-toluenesulfonic acid. Best results are achieved at elevatedtemperatures, for example, between about 50 and l00C. Suitable solventsfor this reaction include, for example, alcohols such as methanol andethanol. and, mixtures of the above with water.

An alternative method for cleavage of the tertiary lower alkyl groupwith concomitant aromatization of the B-ring involves reaction withtrifluoroacetic acid. In

this reaction, the compound of Formula III is treated with an excess oftrifluoroacetic acid, preferably at a temperature between about l0 and+C, most preferably about 0C. It is most advantageous to perform thisreaction in neat trifluoroacetic acid, i.e., without the addition ofother solvents, since trifluoroacctic acid is quite volatile andexcesses can be easily removed and recovered, for example, bydistillation. The initial product obtained from this reaction is the 17-trifluoroacetate of the compound of Formula VII. Due to the lability ofthe trifluoroacetate ester, it is preferred to immediately convert thisproduct during the workup of the reaction to the corresponding 17-hydroxy compound by treatment with water in the presence of a base.

Suitable bases include alkali metal bicarbonates, e.g., sodium orpotassium bicarbonate; alkali metal carbonates, e.g., sodium orpotassium carbonate; or alkali metal hydroxides such as sodium orpotassium hydroxide. Alkali metal hydroxides are preferred. Thishydrolysis is conveniently effected by stirring the crude reactionproduct, after removal of the excess trifluoroacetic acid, with amixture of aqueous base and a suitable water miscible or semi-misciblesolvent. Preferable solvents for this purpose include alcohols such asmethanol and ethanol; ethers such as tetrahydrofuran and dioxane; andketones such as acetone. The crude product of Formula VII can beconverted to equilenin 3-lower alkyl ethers VIII (for example, equileninmethyl ether,

Elli

VIII

' wherein R and R" are as above, by standard oxidation techniques suchas oxidation with a chromium VI reagent, for example, Jones reagent,according to methods known per se.

The present processes may be more fully understood by reference to thefollowing illustrative examples:

EXAMPLE 1 (+)-lB-tert.Butoxy-3a a,4 a -[2-(3-methoxyphenyl)ethyl]7aindanone A solution of 15.7 g (0.1 mole) of m-methoxybenzyl chloridedissolved in ml of anhydrous tetrahydrofuran was added dropwise over aperiod of 1.5 hr. to a rapidly stirred suspension of 9.7 g (0.4 mole) ofmagnesium turnings in I00 ml of anhydrous tetrahydrofuran, with ice bathcooling, under an argon atmosphere. The ice bath was removed and themixture was stirred while warming to room temperature over 1.5 hr. Thesupernatant Grignard solution was then transferred to a clean, dry flaskby filtration through a glass wool plug, under a slight pressure ofargon.

This Grignard solution was cooled to l5 and 0.72 g of powdered cuprouschloride was added. A solution of 4.73 g of(+)-lB-tertiarybutoxy-3aa,6,7,7atetrahydro-7aB-methyl-4-methylene-indan-5(4H)-onein 100 ml of dry tetrahydrofuran was then added with stirring, at l tol0, over a 20 min. period. When the addition was complete, the resultingmixture was immediately poured into 250 ml of vigorously stirredsaturated NH Cl solution. The organic layer was separated and theaqueous layer was extracted with ether. The organic phases werecombined, dried (Na SO filtered and concentrated as aspirator pressure.The residual oil was dissolved in benzene, washed with water and brine,dried again over anhydrous MgSO filtered and concentrated in vacuogiving 15.18 g of a mobile, pungent-smelling oil. This material washeated on a steam bath at 0.01 mm for 30 min. to afford 9.47 g of aviscous oil.

This material was chromatographed on 50 parts of silica gel. Elutionwith 49:1 benzenezethyl acetate gave 1.94g (32.1 of oily product [M25.85(CHCl c 1.18).

An analytical sample was obtained by preparative thin layerchromatography followed by evaporative distillation giving a pale yellowoil, b.p. 190200 (bath)/0.01 mm: [a],, 27.46(c 1.038, CHCI Anal. Calcdfor C H O C,77.05; l-l,9.56 Found: C,76,73; H973 EXAMPLE 2 (+)-l7B-tert. Butoxy-3-methoxyestra-l,3,5(10),9(11)- tetraene A solution of1.56g (0.0435 mole) of product prepared as in Example 1 in 150 ml ofmethanol was stirred rapidly, under nitrogen, while 30 ml of aqueous 10N l-lCl was added in a period of 3 min. After stirring at roomtemperature for 3 hrs. and then with ice bath cooling for 30 min., theresultingslurry was filtered. The solid was washed three times with mlportions of water and dried under vacuum giving 0.95g (64.3%) of solidproduct m.p. 128-129; [01],, 90.99 (c 1.065, CHCIS); uv max (CH OH) 261mg (616700).

Recrystallization of a sample from methanol gave colorless needles, mp.133-134: [c21 101.27 (c 1.0526, Cl-lCl uv max (95% EtOH) 264 nm (619700), inf. 290-300 (e 3550). A portion ofthis material was sublimedprior to combustion analysis at l15-l20/0.02 mm giving colorless solid,mp. 132-133.

Anal. Calcd for C l'l O z C,81.13; 11,9. I Found: C,81.01; H,9.

EXAMPLE 3 This material was dissolved in 10 ml ofice-coldtrifluoroacetic acid. The resulting yellow solution was kept at 0, undernitrogen for 20 hr. then concentrated at aspirator pressure (30). Theresidue was made alkaline with aqueous 0.5 N KHCO solution (135 ml) andstirred at room temperature for 3 hr. after the addition of 20 ml oftetrahydrofuran. Extraction with methylene chloride gave 0.77g of3-methoxy-l7/3- trifiuoroacetoxy-estra-l 3,5(10)-triene, whichcrystallized on standing. ir: (neat) 1780 (ester) cm.

This product was dissolved in a mixture of 20 ml of methanol and 5 ml of10% aqueous NaOH. The resulting solution was stirred at room temperaturefor 1 hr.

whereupon an additional 5 ml of 10% NaOH and 10 ml of methanol wereadded and stirring was continued for 1.75 hr. The mixture was thentreated with brine and extracted with three portions of methylenechloride. The combined methylene chloride extracts were washed withbrine, dried (MgSO filtered and concentrated giving 0.567g of estradiol3-methylether as a pale yellow foam. ir: (neat) 3400 cm (01-1).

Without purification, this compound was dissolved in 20 ml of acetoneand the solution was stirred with ice bath cooling while 0.65 ml ofstandard Jones reagent was added over 3 min. After stirring for 5 min.with ice bath cooling, the excess oxidant was decomposed by the additionof 2 ml of 2-propanol followed by 40 ml of ice-water. The acetone wasremoved at aspirator pressure and the residue was extracted three timeswith methylene chloride. The organic extracts were combined, washed withNal-lCO solution and brine then dried (MgSO filtered and concentrated atreduced pressure giving 0.537g of crude estrone methyl ether, as ayellow solid. Chromatography on 50g of silica gel gave 0.35 (61.7%) ofessentially pure estrone methyl ether (off-white'solid; eluted with 4:1and 2:1 hexane:ether). Recrystallization from acetonitrile gavecolorless solid, mp. 164167; [01],, +153.98 (c 1.00 dioxane); m.m.p.with authentic (+)-estrone methyl ether ([01],, +159.16 (c 1.00dioxane)) 164-l67.5.

EXAMPLE 4 (+)-Equilenin Methyl Ether A 0.34 g (1.0 mmole) sample of pureestratetraene prepared as in Example 2 was added to 5ml of stirred,ice-cold trifluoroacetic acid in an argon atmosphere. Argon was bubbledthrough the resulting yellow-green solution for 10 min. then the flaskwas stoppered and the reaction mixture was kept at 0 for 22 hr.

The trifluoroacetic acid was evaporated at 23 (reduced pressure) givingan orange oil that was immediately dissolved in 25 ml of tetrahydrofuranand treated with 25 ml of 0.5 N aqueous KHCO (pH 9). The resultingmixture was stirred at room temperature for 1.5 hr. Evaporation of thetetrahydrofuran at reduced pressure was followed by extraction withthree portions of chloroform. The organic extracts were combined, dried(MgSO filtered and concentrated at aspirator pressure giving 0.285 g of(+)-3-methoxy-l7B-hydroxyestra-1,3,5(10),6,8-pentaene: uv max (CH OH)225 nm (a 28400), 268 (3340), 277 (3970), 287 (3230), 309 (1460), 322(1500), 337 (1400).

This crude alcohol was dissolved in 10 ml of acetone and the resultingsolution was stirred and cooled in an ice bath while 0.5 ml of Jonesreagent (Go -H was added dropwise. After stirring for 5 min. the excessoxidant was decomposed with 1 m1 of 2-propanol. The

resulting mixture was treated with ice water and most of the acetone wasevaporated at reduced pressure. Extraction of the residual suspensionwith three portions of chloroform followed by washing the extracts withsaturated Nal-lCO solution then drying (MgSO filtration andconcentration at aspirator pressure gave 0.262g of partiallycrystalline, crude equilenin methyl ether. A combination of preparativethin layer chromatography (silica gel; benzene: ethyl acetate, 95:5) andrecrystallization from methanol gave 0.0775g (27.6%) of colorlessneedles, mp. 192-194 which was essentially pure equilenin methyl ether.Another recrystallization from methanol gave colorless solid, mp.l95-196, [M 88.72 (c 0.86, dioxane).

EXAMPLE 5 (+)-l7B-Hydroxy-3rnethoxyestra-l,3,5,(10),6,8- pentaene A1.037g (3.05 mmoles) sample of estratetraene prepared as in Example 2was dissolved in ml of ice cold trifluoroacetic acid and the resultingbrown solution was kept at 0, under nitrogen, for hr. then evaporated ataspirator pressure. The residue was dissolved in 50 ml of methanol andstirred with ice bath cooling while ml of aqueous 10% NaOH solution wasadded followed by an additional ml of methanol. After stirring at roomtemperature for 4 hr., the solution was poured into brine. The mixturewas then extracted three times with methylene chloride. The organicextracts were combined, washed with brine, dried (MgSO filtered andconcentrated at reduced pressure giving 0.853g of a brown foam.

This crude product was chromatographed on 100g of silica gel. Elutionwith 9:1 benz'enezether afforded 0.255g of a gummy solid which wasrecrystallized from methanol giving 0.08g of pure product as colorlesssolid,m.p. 148-146 [a] +40.16 (c l.00,dioxane).

EXAMPLE 6 A solution of 19.5 g (0.125 mole) of m-methoxybenzylchloridedissolved in 118 ml of anhydrous tetrahydrofuran was added dropwise overa period of min. to a stirred'suspension of6.25 g (0.25 mole) ofmagnesium turnings in 25 ml of anhydrous tetrahydrofuran at refluxtemperature and under'an argon atmosphere. The mixture was then stirredfor 30 min. at reflux temperature. After cooling at room temperature,250 ml anhydrous tetrahydrofuran and 11.9 g (0.062 mole) cuprous iodidewere added and the mixture stirred for 5 min. The mixture was thencooled to 20C and allowed to react under stirring at 20C over a 5-hourperiod. A solution of 4.5 g (0.019 mole) of (+)-1,B-tert.butoxy-7aB-methyl-4-methylene-3aa,6,7,7a-tetrahydroindan-5(4l-l)-one in ml of anhydrous tetrahydrofuranwas then added with stirring at 15C over a 30 min. period. When theaddition was complete, the resulting suspension was poured into astirred mixture of 150 ml. of saturated NH Cl solution and 100 g of ice.After stirring for 20 min., the mixture was filtered on Speedex and theresidue was washed three times with 100 ml portions of ethyl ether bysuction. The organic layer was separated and the aqueous layer was ex-200 parts of silica gel. Elution with 50:1 benzenezethylacetate afforded6.025 g of (+)-1 ,8-tert.-butoxy-4-[2-(3-methoxyphenyl)ethyl]-7aB-methy1-3aa,4,7,7a-tetrahydroindan-5(6l-l)-oneas a viscous oil.

EXAMPLE 7 A solution of 5.8 g (0.025 mole) of mbenzyloxybenzyl chloridedissolved in 25 ml of anhydrous tetrahydrofuran was added dropwise overa period of 30 min. to a stirred suspension of 1.25 g (0.05 mole) ofmagnesium turnings in 5 ml of anhydrous tetrahydrofuran at refluxtemperature and under an argon atmosphere. The mixture was then stirredfor 30 min. at reflux temperature. After cooling at room temperature,100 ml of anhydrous tetrahydrofuran and 0.96 g (0.005 mole) of cuprousiodide were added and the mixture was stirred for 2 hours at 20C. Asolution of 1.113 g (0.0047 mole) of (+)-1B-tert.butoxy-7aB-methyl-4-methylene-3aa, 6,7,7a-tetrahydroindan- 5(4H)-one in 10 ml ofanhydrous tetrahydrofuran was then added with stirring at -20C over a 10min. period. When the addition was complete, the resulting suspensionwas poured into a stirred mixture of 50 ml 1 N sulfuric acid and 50 g ofice. After stirring for 5 min., the mixture was extracted three timeswith 100 ml of ethyl acetate. The organic phases were combined, washedwith saturated sodium chloride solution, dried over anhydrous sodiumsulphate, filtered and concentrated on the Rotavap at 50C bathtemperature under water pump vacuum. The residual oil containing (+)-1B-tert.butoxy-3a a,4,7,7a-tetrahydro-4-[2-(3-benzyloxyphenyl)-ethyl]-7aB-methyl-5(6H)-indanone (5.7 g) was dissolvedin 250 ml of methanol, 50 ml of l N hydrochloric acid and 100 ml ofdichloromethane and stirred over a 12-hour period at room temperature.The resulting mixture was poured into 500 ml of water and extractedthree times with 200 ml of dichloromethane. The organic extracts werecombined, dried over anhydrous sodium sulphate, filtered andconcentrated at 40C under water pump vacuum. The residual oil (5.356 g)was chromatographed on parts of silica gel suspended in nhexane. Elutionwith a 1:1 mixture (v/v) of n-hexane and dichloromethane gave 0.995 g of(+)-3-benzyloxy- 1 7B-tert.-butoxy-estra- 1,3,5(10),9(1 l )-tetraene,which after crystallization from methanol melts at 84-85C; [01],, +62 (c0.1, dioxane).

EXAMPLE 8 A solution of 78 g (0.5 mole) of m-methoxybenzyl chloridedissolved in 430 ml of anhydrous tetrahydrofuran was added dropwise overa period of 55 min. to a stirred suspension of 24.3 g (1 mole) ofmagnesium turnings in 100 ml of anhydrous tetrahydrofuran at refluxtemperature and under an argon atmosphere. The

mixture was then stirred for 30 min. at reflux temperature. Aftercooling at room temperature, 2000 ml of anhydrous tetrahydrofuran and15.85 g (0.16 mole) of cuprous iodide were added and the mixture wasstirred for 30 min. at room temperature. A solution of 23.6 g

mole) of (+)-lB-tert.-btuoxy-7aB-methyl-4-methylene-3aoz,6,7,7a-tetrahydroindan-5(4H)-one in 200 m1 of anhydroustetrahydrofuran was then added with stirring over a 15-min. period. Whenthe addition was complete, the resulting suspension was poured into astirred mixture of 1,000 ml of l N sulfuric acid and 1000 g of ice.After'stirring for 5 min., the mixture was sulphate (1 extracted threetimes with 1,000 ml of ether. The organic phases were combined, washedthree times with 500 ml of water, dried over 600 g of anhydrous sodiumhour), filtered and concentrated at 40-45C bath temperature under waterpump vacuum. The residual oil, 80 g, was dried at this temperature for15 min. under a vacuum of 1 1 Torr and then dissolved in 3000 ml ofethanol. Within 15 min., 600 ml of 10 N hydrochloric acid were addedwith cooling, the temperature not exceeding 20C. The faintly turbidsolution was stirred at 20C for 4 hrs and then allowed to stand at atemperature of C for 12 hrs. The suspension was filtered by suction, theresidue being washed five times with 1000 ml of water and dried at80C/l5 Torr for 4 hrs. The crude crystals were dissolved in 200 ml ofether, the solution was diluted with 300 ml of ethanol, then 200 ml ofthe solvent was distilled off. The residual solution was left at 20C for2 hrs during which period crystallization occurred. The crystals werefiltered off with suction, washed with a total of 100 ml of icecoldmethanol and dried at 25C (3 hrs. at 1 1 Torr and 9 hrs. at 0.01 Torr).24.15 g of 17B-tert.-butoxy-3- methoxy-estra-1,3,5(),9(11)-tetraene wereobtained, melting point 131-132C.

EXAMPLE 9 (+)-1B-tert.Butoxy-7aB-ethyl-3aa,4a7,7,a-tetrahydro-4,8-[2-(3-methoxyphenyl)ethyl]-5(6l-l)-indanone and(+)-1B-tert.Butoxy-7aB-ethyl-3aa,4/3,7,7a-tetrahydro-4a-[2-(3-methoxyphenyl)ethyl]-5(6H)-indanone A 4.96 g (0.2 mole) sampleof magnesium turnings was heated at 120 for 0.5 hr then cooled to roomtemperature whereupon ml of dry THF was added. The resulting slurry wasstirred and heated at reflux while a solution of 15.6 g (0.1 mole) ofm-methoxybenzyl chloride in 85 ml of dry THF was added dropwise over a 2hr period. After stirring at reflux for 0.5 hr, the dark mixture wascooled to (ice bath) and 400 ml of dry THF was added followed by 3.17 g(0.032 mole) of cuprous chloride powder. A 6 exotherm' was noted uponaddition of the cuprous chloride. The resulting mixture was stirred atroom temperature for 0.75 hr then a solution of 5.01 g (0.02 mole) ofcrude (+)-1B-tert.butoxy-7aB-ethyl-3aa,6,7,7a-tetrahydro-4-methylene-indan- 5(4l-l)-one in 40 mlof dry THF was added over a 15 c8 min period. After stirring at roomtemperature for 5 min, the resulting solution was decanted from theresidual metal into a stirred mixture of 200 ml of 1 N aqueous H SO and200 g of ice. Stirring was continued for 5 min then ether was added andthe organic layer was separated. The aqueous layer was extracted fourtimes with ether then the organic solutions were combined, washed withwater and brine and dried. Concentration in vacuo afforded 17.2 g ofresidue.

This material was chromatographed on 400 g of silica gel. The earlyfractions eluted with 9:1 hexanezether afforded 3.16 g of the 48H epimerin essentially pure form as a viscous oil. A sample of this material wasrechromatographed on silica gel and evaporatively distilled giving theanalytical specimen as a viscous, paleyellow 011, bp l60-l80(bathtemperature) 0.2 mm. [01],, +11.93(c. 1.2488, CHCl ir (CHCl 1705, 1600,1585 cm; uv max (95% EtOH) 217 nm (e 7946), 272 (1980), 278 (1860); nmr(CDCl,) 8 7.15 (m, 1), 6.72 (m, 3), 3.75 (s, 3), 3.48 (t, 1, J=8 Hz),1.12 ppm (s); ms m/e 372 M*).

Anal. Calcd for C H O,: C,7 38;

The later fractions eluted with 9:1 hexanezether yielded 1.4 g of amixture of the 4 B-H epimer (minor; less polar on tlc) and the 4a-Hepimer (major; more polar on tlc). This material was rechromatographedon silica gel. Later fractions eluted with 9:1 hexane: ether furnished0.51 g of essentially pure (tlc) 4 a-H epimer as a viscous, colorlessoil. [01],, +17.96 (c 1.0468, CHCl uv max EtOH) 215 nm (e 7970), 273(1990), 279 (1870); ir (Cl-lCl 1700, 1600, 1585 cm; nmr (CDCl;,) 8 7.15(m, l), 6.70 (tn, 3), 3.75 (s, 3), 3.43 (m, 1), 1.10 ppm (s); ms m/e 372(M Anal. Calcd for C H O C,77.38; H,9.74 Found: C,77.53; H,9.84

EXAMPLE 10 Epimerization of 4a-l-l epimer A 54 mg sample of 4a -H epimerfrom Example 9 was treated with 5 ml of a solution prepared by diluting5 ml of 1 N aqueous NaOH to 50 ml with methanol. The mixture was heatedfor 5 min. on a steam bath in order to effect solution. After cooling toroom temperature, tlc analysis indicated that'epimerization was completeas evidenced by the essential absence of the spot due to the more polar,4a-l-l epimer. After standing at room temperature for 1.25 hr, thesolution was diluted with methylene chloride and toluene then dried,filtered and concentrated in vacuo. There was obtained 54 mg ofcolorless oil, the tlc mobility of which was identical to that of the48+! epimer. The latter substance was unchanged by alkali treatment.

EXAMPLE 1 l (+)-l7,B-tert.Butoxy-13B-ethyl-3-methoxygona- -1,3,5(10),9(1 1)-tetraene V A solution of 7.28 g (19.6 mmole) of (+)-1B-tert.butoxy-7aB-ethyl-3aa,4B,7,7a-tetrahydro-4a-l2-(3-methoxyphenyl)ethyl]-5(6H)-indanone in 675 ml of methanol was stirredat room temperature while 135 ml of 10 N aqueous HCl was added dropwiseover a 0.5 hr. period. The temperature rose to 34 during the addition.The resulting cloudy mixture was seeded with an authentic crystal ofproduct and stirred at room temperature for 4hr during which time asolid precipitated After cooling to 5 (ice bath) and stirring for anadditional 15 min, the slurry was filtered with suction and the solidwas washed with water. The solid was then dried under high vacuum at40-50 overnight giving 5.86 g of colorless solid, mp. 116-119", [01],,+92.l0(c 1.0239, CHCl3); uv max (95% EtOH) 263 nm (e20000), sh 297(3600), infl 310 (2100). A lg sample of this material was recrystallizedfrom ethanol giving 0.91 gv of colorless needles, mp 120-121. [01],,+97.13(c 1.0285, CHCI uv max (95% EtOH) 263 nm (19780), 298 (3150), infl310 (2120); ir (CHCl 1640, 1615, 1580, 1505, 1375, 1245 cm"; nmr (CDCl)8 7.45 (d, 1), 6.63 (m, 2), 6.06 (m, 1),

3.73 (s, 3), 3.58 (m,1), 1.14 ppm (s); ms m/e 354 Anal. Calcd for C ,,HO C,81.31; 11,9.

Found: C,81.37; H 9

EXAMPLE 12 (+)-17B-tert.Butoxy-13/3-ethyl-3-methoxygona- 1,3,5()-trieneA mixture of lg (2.82 mmoles) of (+)-17[3-tert.butoxy-13B-ethyl-3-methoxygona- 1,3,5(10),9(11)-tetraene, 0.25 g of5% palladium on carbon and 35 ml of ethyl acetate was stirred in anatmosphere of hydrogen for 1 hr during which time a total of 74 ml ofhydrogen was absorbed (70.5 ml theory). The catalyst was filtered withsuction on Celite and the filter cake was washed well with ethylacetate. Concentration of the combined filtrate and washes in vacuo gave1.23 g of colorless solid. This material was chromatographed on 50 g ofsilica 'gel. Elution with 19:1 hexane:ether gave 0.925 g of colorlesssolid which was recrystallized from ethanol. This afforded 0.67 g ofcolorless plates, m.p. 12l123. [01] +44.69(c 1.016, 01-101, uv max (95%EtOH) 278 nm (c2020), 287 (1860); ir (Cl-1Cl 1610, 1580, 1-500, 1360emf; nmr(CDCl )87.18 (m,'1), 6.68 (m, 2) 3.74 (s, 3), 3.51 (t, 1, 11-l2), 1.15 ppm (s); ms m/e 356 (M Anal. Calcd for C I-1 0,: C,80.85;11.10.18 Found: C.80.7l; 11.10.17

EXAMPLE 13 urated aqueous sodium bicarbonate solution then extractedtwice with ether. The combined organic extracts were dried, filtered andconcentrated in vacuo giving 0.348 g of (+)-17B7hydroxy-13B-ethyl-3-methoxygona-l ,3,5( l0)-triene as a colorless solid.

This material was dissolved in 10 ml of acetone and the resultingsolution was stirred with ice bath cooling while 0.4 ml of Jones reagentwas added dropwise from a syringe over a 5-min. period. After stirringat 0-5 for 2 min., the red mixture was decomposed by the addition of 10%aqueous sodium bisulfite solution. The resulting green mixture wasdiluted with water and extracted three times with ether. The etherextracts were combined, washed once with brine then dried, filtered andconcentrated in vacuo giving 0.334 g of crude product as a tan solid.This material was chromatographed on20 g of silica gel. Fractions elutedwith 4:1 hexane:ether afforded 0.274 g of colorless solid.Recrystallization from 1:1 cyclohexane:ethyl acetate furnished 0.207 gof colorless plates, m.p. l48.5 -150. [a],,+102.37(c 1.0257, CHCl);+102.82(c 1.0329, 1:1 cl-lCl zCl-l OH).

EXAMPLE l4 (+)-17B-tert.Butoxy-3-methoxyestra-1,3,5(10)-triene A mixtureof 0.8 g (2.35 mmoles) of (+)-17B-tert.butoxy-3-methoxyestra-1,3,5(10),9(1 1 )-tetraene, 0.25 g of 5%palladium on carbon and 30 ml of ethyl acetate was stirred in anatmosphere of hydrogen for 1.33 hr. At the end of this time, 61 ml ofhydrogen had been absorbed (59 ml theory). The catalyst was filteredwith suction on Celite and the filter cake was washed with ethylacetate. The filtrate and washes were combined and concentrated in vacuogiving 0.831 g of colorless oil which crystallized on standing at 0.Recrystallization from ethanol yielded 0.433 g of product as colorlesscrystals, m.p. 9192.5; ir. (CHCl 1610, 1580, 1500, 1360 cm"; uv. max(95% EtOI-l) 277 (@2030), 285 (1900); nmr (CDCl;,) '0 7.20 (m, 1), 6.63(m, 2), 3.73 (s, 3), 3.43 (t, 1,J=8 Hz), 1.15 (s), 0.75 ppm (s, 3); msm/e 342 (M*). A sample of this material was sublimed (-120/0.15 mm)prior to combustion analysis giving colorless solid m.p. 9092. [01],+62.20(c 1.0176, CHC1 Anal. Calcd for C H O C,80.65; H, Found: C,80.88;H,

I claim: 1. A process for the preparation of a-compound of the formulawherein R is lower alkyl, R is tertiary lower alkyl or a group of theformula wherein R and R are as above, with a compound of the formula R"OCH M wherein R? is as above and M is magnesium halide, lithium, orcopper, in an inert organic solvent and, where M is magnesium halide orlithium, in the presence of cuprous ion, and hydrolyzing the product inan aqueous medium.

2. The process of claim 1 wherein R is methyl or ethyl, R" is methyl andR is tertiary butyl.

3. The process of claim 1 wherein M is magnesium halide.

4. The process of claim 1 wherein the temperature is between about -30and +30C.

5. The process of claim 1 wherein the inert organic solvent comprises anorganic ether.

6. A compound of the formula OR R V wherein R is lower alkyl, R istertiary lower alkyl, or a group of the formula wherein R is hydrogen orlower alkyl, R and R taken independently is lower alkyl, and R is loweralkyl, tertiary lower alkyl, benzyl, diphenylmethyl or trityl.

7. The compound of claim 6 which is lB-tert.butoxy-3aa,4,7,7a-tetrahydro-4-[2-(3-methoxyphenyl)ethyl]7a,B-methyl-5(6H)-indanone.

8. The compound of claim 6 which is lB-terLbutoxy-3aa,4,7,7a-tetrahydro-4-[2-(3-methoxyphenyl)ethyll-7a/3-ethyl-5(6H)-indanone.

9. The compound of claim 6 which is lB-tert.butoxy-3aa,4,7,7a-tetrahydro-4-[2-(3-benzyloxyphenyl)ethyl]-7aB-methyl-5(6H)-indanone.

1. A PROCESS FOR THE PREPARATION OF A COMPOUND OF THE FORMULA
 2. Theprocess of claim 1 wherein R is methyl or ethyl, R'''' is methyl and R''is tertiary butyl.
 3. The process of claim 1 wherein M is magnesiumhalide.
 4. The process of claim 1 wherein the temperature is betweenabout -30* and +30*C.
 5. The process of claim 1 wherein the inertorganic solvent comprises an organic ether.
 6. A compound of the formula7. The compound of claim 6 which is 1 Beta -tert.butoxy-3a Alpha,4,7,7a-tetrahydro-4-(2-(3-methoxyphenyl)ethyl)7a Beta-methyl-5(6H)-indanone.
 8. The compound of claim 6 which is 1 Beta-tert.butoxy-3a Alpha ,4,7,7a-tetrahydro-4-(2-(3-methoxyphenyl)ethyl)-7aBeta -ethyl-5(6H)-indanone.
 9. The compound of claim 6 which is 1 Beta-tert.butoxy-3a Alpha,4,7,7a-tetrahydro-4-(2-(3-benzyloxyphenyl)ethyl)-7a Beta-methyl-5(6H)-indanone.